Hydrogel-Based Materials for Delivery of Herbal MedicinesWing-Fu Lai*,†,‡ and Andrey L. Rogach§

†Department of Pharmacy, Health Science Center, Shenzhen University, Shenzhen 518060, China‡Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong§Department of Physics and Materials Science and Centre for Functional Photonics, City University of Hong Kong, Hong Kong

ABSTRACT: Herbal medicine, as an integral component oforiental medicine, has assimilated into the lives of Asian peoplefor millennia. The therapeutic efficiency of herbal extracts andingredients has, however, been limited by various factors,including the lack of targeting capacity and poor bioavailability.Hydrogels are hydrophilic polymer networks that can imbibe asubstantial amount of fluids. They are biocompatible, and mayenable sustained drug release. Hydrogels, therefore, haveattracted widespread studies in pharmaceutical formulation.This article first reviews the latest progress in the developmentof hydrogel-based materials as carriers of herbal medicines,followed by a discussion of the relationships between hydrogel properties and carrier performance. Finally, the promisingpotential of using hydrogels to combine medicinal herbs with synthetic drugs in one single treatment will be highlighted as anavenue for future research.

KEYWORDS: hydrogels, oriental medicine, drug delivery, herb, sustained release

1. INTRODUCTION

Herbal medicine is an integral component of oriental medicine.Attributed to the prospect of drug discovery from medicinalherbs, the therapeutic potential of herbal medicine has begun tobe recognized globally. One example of drugs discovered fromherbal medicines is Kanglaite, which is an investigationalanticancer drug extracted from Semen coicis. The injectable formof Kanglaite has been approved in China for treating cancers.1

Another example is ephedrine. It is a sympathomimetic amineisolated from Ephedra vulgaris. This drug has been commonlyused as a cardiac stimulant, a bronchodilator, and a hyper-glycaemic agent.2 From vision enhancement with Lyciumbarbarum fruits to cancer treatments,3−6 herbal medicine hasassimilated into the lives of Asian people for millennia. Despitethis, the therapeutic efficiency of herbal medicines has beenhindered by various factors, including the lack of targetingcapacity and poor bioavailability. Furthermore, because of thevariations in structures and physicochemical properties ofdifferent bioactives in herbal medicines, the efficiency ofabsorption and cellular internalization of those bioactives,which are integral parts of the herbal treatment, may varygreatly, reducing the treatment efficacy.To solve these problems, one possible strategy is to adopt a

carrier to facilitate the delivery of herbal bioactives. As a matterof fact, various materials (including lipids and hydrogels) havealready been developed over the years for drug deliverypurposes.7−10 While there is an upsurge of reviews summarizingthe applications of these materials in the delivery of syntheticdrugs, the possible use of these materials in formulating herbalmedicines has rarely been put to formal discussions in the

literature. This article attempts to fill this gap by highlightingthe possible incorporation of current drug delivery technolo-gies, with a special focus on hydrogels, into herbal treatment,and examining how the properties of hydrogels can be tailoredto enhance the delivery efficiency of herbal medicines.

2. STRENGTHS OF HYDROGELS FOR DELIVERY OFHERBAL MEDICINES

Hydrogels are swellable networks that can absorb a substantialamount of fluids. Their major constituents are polymers, whichcan be natural or synthetic in origin. One important naturalpolymer for hydrogel synthesis is alginate (Alg). It is an anionicpolysaccharide consisting of (1−4)-linked β-D-mannuronicacid and α-L-guluronic acid.11−17 Upon gelation with simpledivalent ions (e.g., Ca2+), Alg can form matrices for beads, gels,microparticles, and nanospheres.18,19 Another example ofnatural polymers is collagen, which is a major constituent ofthe extracellular matrix of the connective tissue. Collagen hashigh mechanical strength.20 It has been used to fabricatehydrogels for tissue engineering21 and corneal applications.22

Other common examples of natural polymers for hydrogelsynthesis are chitosan (CS),23 gelatin,24 agarose,25 andhyaluronic acids.26 Apart from natural polymers, advances inmaterials science have led to the development of diversesynthetic polymers for hydrogel formation, including poly(N-vinylpyrrolidone) (PVP),27 poly(2-hydroxyethyl methacrylate)

Received: December 15, 2016Accepted: February 28, 2017Published: February 28, 2017

Review

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© 2017 American Chemical Society 11309 DOI: 10.1021/acsami.6b16120ACS Appl. Mater. Interfaces 2017, 9, 11309−11320

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(PHEMA),28−30 poly(N-isopropylacrylamide) (PNIPAM),31,32

and poly(ethylene glycol) (PEG).33,34 Compared to naturalpolymers, synthetic polymers and their derivatives usually havehigher mechanical strength; however, there are concerns abouttheir toxicity and poor biodegradability. Current research isseeking to generate a hybrid polymer by combining theadvantages of both natural and synthetic materials for hydrogelfabrication. In an earlier study, dextran has been copolymerizedwith lactic acid oligomers.35 By using this approach, thehydrogel obtained is fully degradable under physiologicalconditions. This is because degradation can occur via eitherrandom hydrolysis of the ester bonds in the lactate grafts, orcleavage of the lactate grafts from the dextran backbone by theattack of OH−.35 Many of the related efforts have beenreviewed elsewhere.36−41 Readers are directed to those reviewsfor details.Compared to other systems developed for delivery of herbal

medicines (Tables 1a and 1b),42−46 a unique strength possessedby hydrogels is the high water absorption capacity.47 Thiscapacity has favored the loading of herbal medicines, which aregenerally aqueous in nature, into hydrogels. With advances inmaterials design, some hydrogels have also been reported toallow for prolonged and stimuli-controlled drug release.8,48 Anoverview of the important properties of hydrogels for deliveryof herbal medicines is provided in Figure 1. The possibility ofusing hydrogels as carriers of herbal medicines has beendemonstrated by Lim et al.,49 who have prepared a hydrogelpatch containing two herbal extracts for treatment of atopicdermatitis (AD). The first extract is from Ulmus davidiana var.japonica (UD), which is a deciduous broad-leaved treecommonly found in oriental countries. Its root bark and stemhave been found to be therapeutic to mastitis, cancers,inflammation, edema, and rheumatoid arthritis.50 The secondone is from Houttuynia cordata Thunb. The extract has beenused to treat herpes simplex,51 chronic sinusitis,52 and nasalpolyps.52 It has also been reported to have anticancer,53

antioxidant,54 and adjuvant activities.55 A hydrogel patchcontaining the two extracts has been fabricated by “freezingand thawing” and 60Co γ-ray irradiation.49 Because of themoisturizing effects and the activity of the extracts on atopicwounds, mice treated with the patch have effectively recoveredfrom edema led by contact dermatitis (Figure 2),49 and havesuffered from less itchiness caused by AD.49 In addition, thepatch can be attached to or detached from the skin easily.49

This makes clinical applications of the patch more viable.The promising potential of using hydrogels to deliver herbal

medicines has been further supported by a recent study,56 inwhich a solid lipid nanoparticle (SLN)-enriched hydrogel hasbeen reported for topical delivery of astragaloside IV, which is amajor constituent of Astragalus membranaceus. The hydrogelhas enabled sustained release of astragaloside IV, and hasenhanced the migration and proliferation of keratinocytes invitro.56 In a full-skin excision rat model, the hydrogel has beendemonstrated to increase the wound closure rate. It has alsofacilitated angiogenesis and collagen deposition (Figure 3).56

These have rendered the hydrogel-based system viable for useas a wound management product. As a matter of fact, over theyears, the possible use of hydrogels loaded with herbalmedicines has already been exploited in diverse areas, fromproduct development to disease treatment (Table 2).46,57−69

For the latter, the clinical potential has been evidenced inclinical trials. A good example has been provided by arandomized, double-blind, placebo-controlled clinical trial Table

1a.Someof

theDeliverySystem

sExploited

intheLiterature

forDeliveryof

HerbalMedicines:Phytosomes

andLiposom

es

Use

deliverysys-

tem

descrip

tion

strengths

limitatio

nsexam

ple

ref

phytosom

esphytosom

esareusually

prepared

bycomplexationbetweenphosphatidyl-

cholineandpolyphenolicphytocon-

stituents

•comparativelysafeandbiocom

patible

•poor

storagestability

phytosom

eshave

been

fabricated

with

silybin,

which

isthemostpotent

flavonoidin

thefruitof

themilk

thistle

plant(Silybum

marianum);comparedto

conventio

nalsilymarin,the

phytosom

eshave

exhibitedenhanced

bioavailabilityandliver

protectio

neffects

42

•canbe

produced

indifferentsizes,

therebyenablingencapsulationof

molecules

with

diversesize

ranges

•laborio

usproductio

nproce-

dures

•poor

encapsulationeffi

ciency

liposom

esliposom

esareconstructedof

phospho-

lipids;they

canencapsulateboth

hydrophilic

andhydrophobicmole-

cules

•co-deliveryof

both

hydrophilic

and

hydrophobicmolecules

hasbeen

madepossibleusingmultilayered

liposom

es

•poor

storagestability

liposom

eshave

been

adoptedto

enhancetheinhibitory

effectof

diospyrin

,abisnaphthoqui-

nonoid

plantproduct,on

tumor

grow

th;comparedto

thosetreatedwith

thefree

drug,the

tumor-bearin

gmicetreatedwith

liposom

aldiospyrin

have

been

reported

tohave

enhanced

longevity

43

•canbe

produced

indifferentsizes,

therebyenablingencapsulationof

molecules

with

diversesize

ranges

•laborio

usproductio

nproce-

dures

•poor

encapsulationeffi

ciency

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Table1b.Som

eof

theDeliverySystem

sExploited

intheLiterature

forDeliveryof

HerbalM

edicines:Polym

ericNanop

articles

andMicroparticles,Emulsion

s,andHydrogels

Use

deliverysystem

descrip

tion

strengths

limitatio

nsexam

ple

ref

polymeric

nanoparticles

andmicro-

particles

polymericnanoparticlesandmicroparticlesgenerally

have

sphericalmorphologies,though

generatio

nof

non-

sphericalparticleshasbeen

reported;durin

gtheloading

process,theagentto

bedelivered

canbe

encapsulated

inside,o

rcanadsorb

ontheparticlesurface

•canoffer

controlledandsustained

releaseof

theencapsulated

mole-

cules

•particle−particleaggrega-

tionmay

occur,lim

iting

the

storagestability

PLAananoparticleshave

been

reported

toimprovethesolubility,perm

eability

andstabilityof

quercitrin,w

hich

isan

antio

xidant

isolated

from

Albiziachinensis

44

•techniques

inpolymer

engineering

have

been

well-established,making

functio

nalizationof

theparticles

(and

hencemodulationof

the

particleproperties)

feasible

•precisecontrolof

the

polydispersity

ofthepar-

ticlesistechnically

chal-

lenging;

thishampers

the

efficiency

ofdrug

delivery

emulsions

emulsionsgenerally

arebiphasicsystem

sin

which

one

phaseisdispersedin

theotherphasein

theform

ofminutedroplets;someem

ulsionsmay

have

morethan

twophases

•comparativelyeasy

inproductio

n•poor

storagestability

quercetin

hasbeen

form

ulated

asawater-in

-oilmicroem

ulsion

toenhanceits

skin

penetration

45

•thephysicsof

emulsion

produc-

tionhasbeen

well-studied,m

aking

engineeringof

theem

ulsion

pro-

ductionprocessfeasible

•dropletsin

emulsionsgen-

erallyarehighlypolydis-

persed;thishampers

the

efficiency

ofdrug

delivery

hydrogels

hydrogelsarehydrophilic

polymer

networks

that

can

imbibe

asubstantialam

ount

offluids

•biocom

patible,and

comparatively

lowin

toxicity

•difficultto

encapsulate

hydrophobicmolecules,o

rto

besimultaneouslyloaded

with

molecules

with

varying

degreesof

hydrophilicity

theSanqib

onepaste,which

isaform

ulationcontaining

herbalmedicines

such

asNotoginseng

RadixetRhizoma(Sanqi)andDipsaciRadix,hasbeen

incorporated

into

ahydrogel;comparedto

theconventio

nalbone

paste,thegenerated

hydrogelpatchhasexhibitedenhanced

transdermalproperties,andhasallowed

formoresustainedreleaseof

theherbalbioactives

46

•possibleto

offer

controlledand

sustainedreleaseof

theencapsu-

latedmolecules

•possibleto

inactivateherbal

componentswhenchem

ical

cross-linking

isinvolved

durin

ghydrogelfabrication

•sophisticated

techniques

inpoly-

mer

engineering,makingfunc-

tionalizationof

polymer

constitu-

ents(and

hencemodulationof

hydrogelproperties)

feasible

aPL

A=poly-D,L-lactide.

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conducted with ambulatory patients.70 In the study, the extractof the Mimosa tenuiflora cortex, which is a popular remedyutilized in Mexico to treat skin lesions, has been incorporatedinto a hydrogel (which has been prepared using Carbopol 940,PEG 200, and triethanol amine) for the treatment of venous legulceration (VLU) disease. The size of the ulcer in patientstreated with the extract-loaded hydrogel has been significantlyreduced (Figure 4), while those treated with the hydrogel alonehave exhibited no significant improvement. Based on theevidence above, it is clear that delivery of herbal medicinesusing hydrogels holds promise for clinical applications.

3. PREPARATION OF HYDROGELS FOR DELIVERY OFHERBAL MEDICINES

Many first-generation hydrogels are principally chemicalhydrogels.71 Some of them have been fabricated by cross-linking hydrophilic polymers such as poly(vinyl alcohol) (PVA)and PEG. Others have been formed via polymerization ofwater-soluble monomers in the presence of a cross-linker. Arepresentative example of the latter case is the poly(acrylamide)hydrogel, which has been exploited initially for physicalentrapment of cells and enzymes72,73 and later for use as softtissue fillers.74 Notwithstanding the track record of applyingchemical hydrogels to drug delivery, using chemical hydrogelsas carriers of herbal medicines might not be favorable. This is

because loading of the herbal medicines is usually performed bysimply mixing the medicines with hydrogel constituents beforecross-linking occurs. Herbal medicines usually contain multiplecomponents and, hence, a variety of functional groups. Sidereactions between the cross-linker and any of thesecomponents may jeopardize the integrity and efficacy of thetreatment.Compared to chemical hydrogels, physical hydrogels may

have lower long-term stability and mechanical strength;however, covalent cross-linkers are not required for theirformation. Side reactions with the herbal components can beminimized.75 This has been demonstrated using the crude leafextract of Hemigraphis alternata. The extract has previouslybeen reported to have anti-inflammatory effects and hasfacilitated wound contraction and epithelialisation in thecarrageenan-induced paw edema mouse model.76 Upon loadinginto a hydrogel, the extract has maintained its hemostatic andantibacterial activities.77 This, together with the effects of theextract-loaded hydrogel in facilitating platelet activation, dermalfibroblast attachment, and blood clotting, has made thehydrogel-based system potentially useful for future woundcare.77

To obtain physical hydrogels, various methods have beenreported. One method is ionic gelation, which is based on

Figure 1. Properties of hydrogels for delivery of herbal medicines.

Figure 2. Photos taken at different stages of the contact dermatitistreatment, in which the hydrogel patch containing extracts of UD andHouttuynia cordata Thunb. has been adopted. (Reproduced withpermission from ref 49. Copyright 2009, Elsevier, Amsterdam.)

Figure 3. Effects of the SLN-enriched hydrogel loaded withastragaloside IV in inducing wound healing: (A) Masson’s trichromestaining at 1, 3, and 7 weeks post-wounding; (B) collagen depositionin the regenerated skin, as examined by scanning electron microscopy(SEM), at 3 weeks post-wounding at different magnifications; and (C)Sirius red staining at 3 weeks post-wounding. In this figure, column Irepresents the blank control group. Columns II, III, and IV have beentreated with the blank SLN-enriched hydrogel, astragaloside IVsolution, and astragaloside IV-loaded SLN-enriched hydrogel,respectively. Column V represents the normal skin. (Reproducedwith permission from ref 56. Copyright 2013 Elsevier, Amsterdam.)

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Table

2.Someof

theApp

lications

ofHydrogelsLo

aded

withHerbalMedicinesa

Exam

ples

area

ofapplica-

tion

principleof

application

polymer

constitu-

ent(s)

form

ofthehy-

drogel

methodof

fabrication

agentto

bedelivered

herb(s)involved

ref

treatm

entof

cu-

taneous

anom

alies

beappliedtopically

toskin

todeliver

herbal

medicines

tothesite

ofinterest

Poloxamer

407,

CMC

bulk

Poloxamer

407hasbeen

addedinto

aCMCsolutio

nin

anicebath

underconstant

magnetic

stirring

herbalextract

PaeoniasuffruticosaAndrews

57

Carbopol940

bulk

Carbopol940hasbeen

dispersedin

water

atroom

temperature,followed

byneutralizationwith

triethanolam

ine

herbalextract

Ipom

eapes-tigrid

is58

tissueengineer-

ing

beloaded

with

herbalmedicines

that

are

thoughtto

facilitatetissueregeneratio

n,andbe

appliedto

theaffectedarea

Alg

bulk

Alg

hasundergoneionicgelatio

nwith

Ca2

+activeingre-

dient

liver-softening

herbs

59

CS

bulk

theCSsolutio

nhasbeen

mixed

with

asolutio

nof

ammonium

hydrogen

phosphate

saltat

4°C

herbalextract

Cissus

quadrangularis

60

wound

healing

beadoptedto

deliver

herbalmedicines

tothe

wound

tofacilitatethewound

healing

process

CS,

PVP,

PNIPAm

film

solutio

nsofCSandPV

Phave

been

mixed,followed

bytheadditio

nofthePN

IPAm

solutio

n;themixed

solutio

nhasthen

been

driedto

form

afilm

herbalextract

Salix

alba

leaves

61

PluronicF-127

bulk

gelform

ationhasbeen

inducedby

elevationof

temperature

herbalextract

Terminalia

arjuna

bark

62

PluronicF-127

bulk

gelform

ationhasbeen

inducedby

elevationof

temperature

activeingre-

dient

Terminalia

arjuna

bark

for

tannins

developm

entof

cosm

eceutical

products

beadoptedto

developskin

care

products

containing

herbalextractsor

ingredients

Carbopol934,Car-

bopol940,Car-

bopol941,xan-

than

gum

bulk

thepolymershave

been

dispersedin

water,followed

byneutralizationwith

NaO

H;

thehydrogelhasbeen

incorporated

with

nanospheresbefore

use

activeingre-

dient

Rhodiolaroseaforsalidroside,

andpeoniesforpaeonol

63

Carbomer

bulk

thepolymer

hasbeen

dispersedin

water,followed

byneutralizationwith

triethanolam

ine

herbalextract

Imperata

cylindrical

64

CarbopolUltrez

20bulk

thepolymer

hasbeen

dispersedin

water,followed

byneutralizationwith

NaO

H;

thehydrogelhasbeen

incorporated

with

ananoem

ulsion

before

use

herbalextract

Achyroclinesatureioides

65

food

productio

nbe

utilizedto

encapsulateherbalcomponents

toimprovethestabilityandfunctio

nalityof

thosecomponentsin

food

products

Alg

beads

Alg

hasundergoneionicgelatio

nwith

Ca2

+herbalextract

Pterospartum

tridentatum

66

Ilexparaguariensis

67

Thymus

serpyllum

L.68

cancer

treat-

ment

beadoptedto

releasetheherbalingredient

tothetumor

site

inasustainedmanner

PECT

bulk

PECThasbeen

used

toform

apowder,in

which

theherbalactiveingredient

has

been

incorporated,viananoprecipitatio

n;thepowderhassubsequentlybeen

dispersedin

salineto

form

asolutio

n,which

canform

agelby

elevationof

temperature

activeingre-

dient

Embelia

ribesBurm

forem

be-

lin69

bone

setting

beused

toreleasetheherbalbioactives

tothe

affectedsite

inasustainedmannerto

facilitatealleviationof

themusculoskeletal

injury

ViscomateNP7

00,

Carbopol940,

PVP,

gelatin

bulk

thepolymershave

been

used

toform

differentphases

bybeingdissolvedin

their

correspondingsolvents;the

phases

have

then

been

mixed

atdifferenttim

epoints

toform

thehydrogelpatch

Herbalfor-

mulation

Panaxnotoginseng,Cartham

ustinctoriusL

.,andotherherbs

used

intheSanqibone

paste

46

aAbbreviations:Alg,alginate;CMC,carboxym

ethylcellulose;CS,

chito

san;

PECT,poly(ε-caprolactone-co-1,4,8-trio

xa[4.6]spiro-9-undecanone)-poly(ethylene

glycol)-poly(ε-caprolactone-co-1,4,8-

trioxa[4.6]spiro-9-undecanone);PN

IPAm,p

oly(N-isopropylacrylam

ide);andPV

P,poly(vinylpyrolidone).

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electrostatic interactions between polymer chains and oppo-sitely charged ions. Some examples of hydrogels generated fromthis method are Ca2+-cross-linked Alg hydrogels and CS-tripolyphosphate (TPP) hydrogels. Another method tofabricate physical hydrogels is stereocomplexation. This hasbeen adopted by an earlier report in which two complementingstereoregular polymers have interacted to display physicalproperties different from either of the two polymers.78 By usingthis method, self-assembled hydrogels have been generatedfrom enantiomeric lactic acid oligomer-grafted dextran (dex-lactate).35 More recently, the sol−gel properties of polymershave been exploited for generation of physical hydrogels toenhance the performance of herbal medicines. This isdemonstrated in a report on a thermosensitive injectablehydrogel fabricated from an amphiphilic triblock copolymer ofpoly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)−PEG−poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undeca-none) (PECT). The hydrogel has facilitated the delivery of anactive herbal ingredient, namely embelin, whose in vivoapplications have been limited by its poor aqueous solubility.The hydrogel has enabled sustained release of embelin.69 Upona single local peritumoral injection of the embelin-loadedhydrogel into a liver at a low dosage of 0.5 mg perhepatocarcinoma-bearing mouse, the antitumor effect attainedhas been found to be comparable to a total dose of 6 mg of freeembelin per mouse.69 This promising result has corroboratedthe possible role of physical hydrogels in boosting the efficacyof oriental herbal medicine.

4. MODULATION OF HYDROGEL PROPERTIES FORDELIVERY OF HERBAL MEDICINES

When carriers of herbal medicines are developed, one of thefactors to be considered is the loading efficiency, which islargely affected by the affinity of the herbal components to thehydrogel matrix. In oriental medicine, one regimen is generallyconsisted of multiple herbs. Therefore, multiple componentsmust be delivered simultaneously in order for the treatment tobe effective. This is technically challenging, because most of the

delivery systems reported in the literature are mainly designedfor use in single drug therapies. Settling this problemnecessitates a hydrogel-based system that can carry herbalcomponents with different degrees of hydrophilicity. Hydrogels,however, are hydrophilic in nature. If the loaded componentsare hydrophobic, the affinity of the components to the hydrogelmatrix will generally be low. The components may simplydiffuse out of the matrix before the loading process is complete,limiting the final loading yield.One strategy to solve this problem is to first encapsulate the

hydrophobic components into a system that shows a higheraffinity to the hydrogel matrix, before the components areloaded into a hydrogel. This approach has been adopted in anin situ gel-forming system, which composes of curcumin-loadedmicelles and a thermosensitive hydrogel. Curcumin is an activecomponent of turmeric (the powdered rhizome of Curcumalonga L.). In China and some Asian countries, it has been usedas a spice, and as a remedy to treat diverse inflammatory andchronic diseases.79 It has also been reported to be effective inwound repair upon oral and topical administration.80,81 Despitethis, the clinical efficacy of curcumin has been limited partly byextensive first-pass metabolism.82 This problem might bealleviated by loading curcumin into hydrogels for moresustained release. Curcumin, however, has low aqueoussolubility.83 Its affinity to the hydrogel matrix is low. Toaddress this problem, curcumin has first been encapsulated inpolymeric micelles.84 The encapsulated curcumin (Cur-M) hassubsequently been loaded into a thermosensitive PEG−poly(ε-caprolactone)−PEG (PEG−PCL−PEG) hydrogel (Figure 5A)to form a system (viz. Cur-M-H) for use as a wound dressing.84

The system is a free-flowing sol under ambient conditions, butcan be converted to a nonflowing gel at body temperature(Figure 5B). Compared to those treated with normal saline,wounds treated with Cur-M-H have exhibited negligible signsof inflammation and infection, and have not had anypathological fluid oozing out (Figure 5C).84 Histopathologicanalysis has revealed that wounds treated with Cur−M−H haveshown a higher degree of re-epithelialization, well-organizedgranulation tissues, and significant fibroblastic deposition,compared to those treated with Cur−M, normal saline, andthe hydrogel containing blank micelles (Figure 5D).84 Thisstudy has demonstrated the feasibility of enhancing theefficiency of the loading process by first encapsulating a herbalingredient in another system before hydrogel encapsulation.To improve the loading efficiency, another method is to

modulate hydrogel properties to increase the affinity of thehydrogel matrix to hydrophobic components. This has beenhinted at in a previous study, in which an Alg-based hydrogelhas been adopted to encapsulate a herbal extract of Pipersarmentosum.85 Hydrogels fabricated from Alg with a highermannuronate/guluronate (M/G) ratio have been shown tohave higher encapsulation efficiency.85 This suggests thatengineering the chemical composition of polymers can be astrategy to facilitate the loading of herbal medicines intohydrogels. Although related efforts are still incipient, thetheoretical plausibility of this strategy has already beendemonstrated by Byrne and co-workers,86 who have useddifferent functional monomers and template molecules togenerate a hydrogel for loading molecules with varying degreesof hydrophilicity. A more recent study has also modified CSwith hypromellose to generate hypromellose-graf t-chitosan(HC) (Figure 6A).8 The copolymer has higher aqueoussolubility than native CS8 and can form a hydrogel upon

Figure 4. Photos of skin lesions in two VLU patents (viz. G.M.M. andS.Z.E.) treated with the hydrogel containing the extract of Mimosatenuiflora. (Reproduced with permission from ref 70. Copyright 2007,Elsevier, Amsterdam.)

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complexation with carboxymethylcellulose (CMC) to physi-cally entrap drug molecules (Figures 6B). In total four drugmodels (viz. mometasone furoate, methylene blue, tetracyclinehydrochloride, and metronidazole) with different degrees ofhydrophilicity have been tested. The drug encapsulationefficiency of the HC/CMC hydrogel has been found to be1−2 times higher than that attainable by the hydrogel formedusing CS (Figure 6C). This has pointed to the prospects ofimproving the loading of components with varying propertiesby optimizing the molecular design of a hydrogel-based system.In addition to the loading efficiency, when a carrier is

developed, another factor to be considered is the releasesustainability. It can be controlled by changing the polymercomposition to modulate the tortuosity and mesh size of thepolymer network,87 the hindrance of polymer chains to drug

diffusion,87 and the swelling property of a hydrogel. This hasbeen illustrated by Patenaude and Hoare,88 who havefunctionalized natural polymers (such as CMC, dextran, andhyaluronic acid) and PNIPAM-based synthetic oligomers withhydrazide or aldehyde functional groups to generate a series ofin situ gelation, hydrazone-cross-linked hydrogels (Figure 7). Bychanging the number and ratio of different reactive oligomersor polymer precursors, hydrogels with different swellingproperties and degradation kinetic profiles have been generated.More recently, a composite hydrogel comprising bothpoloxamer 407 (P407) and CMC has been reported as acarrier of the Cortex Moutan (CM) extract for the treatment ofAD.57 The high moisture content of the P407-based hydrogelhas helped moisturizing the skin of AD patients. Upon theaddition of CMC, the porous structure, the gelation transition

Figure 5. (A) Structural formula of PEG−PCL−PEG, which is used to form Cur−M−H. (B) Preparation and characterization of the Cur−M−Hcomposite ((i) Cur−M−H at 10 °C (left) and 37 °C (right); (ii) dermal adhesiveness of the Cur−M−H composite). (C) Images of skin woundstreated with (i) normal saline, (ii) the hydrogel containing blank micelles, (iii) Cur−M, and (iv) Cur−M−H, on the 14th day of wound healing. (D)The hematoxylin and eosin stained sections of the granulation tissue in groups treated with (i) normal saline, (ii) the hydrogel containing blankmicelles, (iii) Cur−M, and (iv) Cur−M−H, on the 14th day of wound healing. (Reproduced with permission from ref 84. Copyright 2013, Elsevier,Amsterdam.)

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temperature, and the rheological property of the hydrogel havebeen further optimized. Changes in the concentrations of P407and CMC have been shown to lead to changes in the bulkviscosity of the hydrogel-based system and, hence, the releaseprofile of the extract.57 This has revealed the close relationshipbetween the release sustainability and composition of ahydrogel.Last, but not least, high biodegradability and low toxicity are

important prerequisites to be met if a carrier is to be applied toa biological body, but this is particularly a problem in chemicalhydrogels. This problem can be tackled by incorporatingbiodegradable chemical groups or polymer segments into thebackbone of the polymer constituent, as demonstrated in anearlier study in which dextran has been copolymerized withlactic acid oligomers.35 The generated hydrogel has beenreported to be fully degradable under physiological con-ditions.35 A similar strategy has also been adopted in a recentstudy,89 in which the toxicity of poly(ethylenimine) (PEI) hasbeen lowered by graft polymerization with polysorbate 20,generating hydrogel nanoparticles with a higher safety profilefor biological applications.89 Over the years, substantial effortshave been devoted in the literature to generating polymers withlow toxicity and high biodegradability. Many of these effortshave already been reviewed elsewhere.36−41 Readers arereferred to those reviews for details.

5. PROSPECTS AND LIMITATIONS

Oriental medicine and Western medicine are two importantsystems in medical science. Oriental medicine views the humanbody as a microcosm consisting of both internal and externalconditions, emphasizing the equipoise of “energies” in the fivezang-viscera.90 It has the merit of being attentive to the root ofthe medical condition, but is perceived to be slower in action.91

On the other hand, Western medicine confronts the symptomsdirectly and, hence, has quicker effects, but the restoration ofthe internal balance has not been emphasized as much as that inoriental medicine.91 In the light of this, integrating herbalmedicines with synthetic drugs from Western medicine maybecome a future approach in disease treatment. This potentialhas been presented in an earlier study on patients withidiopathic nephrotic syndrome.92 Compared to those treatedwith synthetic drugs (viz. prednisone and Cytoxan) alone,those treated with both synthetic drugs and herbal soups havebeen reported to have a higher remission rate, a lower adversereaction rate, and a longer remission period. Similar promisingeffects have also been documented by Yao et al.,93 who haveintegrated herbal remedies (comprising herbs such asdandelion, giant knotweed, and barbed stullcap) with syntheticdrugs (e.g., cyclosporine A, mycophenolate, prednisone,rapamycin, azathioprine, and tacrolimus) in the treatment of

Figure 6. (A) Schematic diagram showing the synthesis of HC. (B) Schematic diagram illustrating the complexation of HC with CMC. (C)Efficiency of HC/CMC and CS/CMC hydrogels in encapsulating drug molecules with varying degrees of hydrophilicity. Abbreviations: CMC,carboxymethylcellulose; CS, chitosan; HC, hypromellose-graf t-chitosan; MB, methylene blue; MF, mometasone furoate; MT, metronidazole; andTH, tetracycline hydrochloride. (Reproduced with permission from ref 8. Copyright 2015, American Chemical Society, Washington, DC.)

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severe post-kidney-transplant lung infection. Among the 18patients participated in the study, 15 of them have shownpositive outcomes. This has been attributed to the effect of theherbal remedies in increasing the blood neutrophilicgranulocyte phagocytic index and the blood plasma totalcomplementary level in patients, thereby enhancing patients’immune functions to fight against the infection.93

Despite the potential as depicted above, some herbalmedicines and synthetic drugs may be incompatible with eachother. Their combined use may jeopardize the efficacy of thetreatment. This is exemplified by the herb Hypericumperforatum, which induces the expression of cytochrome P450enzymes and P-glycoprotein, ultimately lowering the serumconcentrations of synthetic drugs such as cyclosporine,indinavir, irinotecan, and nevirapine.94 Another study onpulmonary fibrosis rat models has also found that the healthconditions of animals treated with a combined therapyconsisting of azathioprine and Tripterygium wilfordii wereworse than those treated with azathioprine alone.95 Therefore,herb−drug interactions must be taken into consideration whena combined therapy is administered. While further elucidationof the nature of those interactions is desired, if theincompatibility problem is caused by direct interactionsbetween herbal medicines and synthetic drugs, this problemmight be solved by advances in microfabrication technologiessuch as microfluidic electrospray, which has been adopted togenerate multicompartment hdyrogel beads for codelivery ofincompatible agents.7 By using cadmium−telluride (CdTe)quantum dots (QDs) and PEI as a model pair, the beads haveseparated the incompatible agents in different compartmentsduring the delivery process.7 Moreover, the composition of thecompartments can be tuned using the polymer blendingtechnique to attain different release profiles of the codeliveredagents.7 The versatility provided by the beads is expected tobring new opportunities to the development of therapies that

integrate both herbal medicines and synthetic drugs into onesingle system.Finally, it is worth noting that the success of delivering herbal

medicines using hydrogels may be more complicated thanexpected. Much more optimization may be required beforesuccess can be achieved. This is demonstrated in a clinical trialin which a hydrogel containing tepescohuite, which is theextract of the bark ofMimosa tenuiflora, has been studied for thetreatment of VLU disease.96 The study has recruited 41patients, who have topically applied the hydrogel on the ulceron a daily basis. Histologic evaluation, however, has shown thatthe therapeutic effect of the extract-loaded hydrogel is notsignificantly different from that of the blank hydrogel. Thisreveals that successful incorporation of herbal medicines intohydrogels for clinical use may necessitate prior optimizationand careful execution.

6. CONCLUDING REMARKSHerbal medicine is an important part of oriental medicine thathas been gaining recognition and popularity around the world.In this article, we have reviewed the latest advances in thedevelopment of hydrogel-based materials as carriers of herbalmedicines, and have discussed the clinical challenges andpotential for future research. As shown by the evidencepresented, hydrogels are biocompatible materials that can beused as carriers to improve the efficacy of herbal treatments inboth clinical and preclinical studies. This encouraging potentialhas been augmented by advances in microfabricationtechnologies, which enable hydrogel manipulation and makefuture integration of both herbal medicines and synthetic drugsinto one single treatment technically feasible. In the forth-coming decade, rejuvenation and advancement of herbalmedicine are expected to be facilitated continuously byadvances in drug delivery technologies and materials science.What we are looking forward to is the emergence of moreeffective herbal treatments in the foreseeable future.

Figure 7. Schematic diagram showing the synthesis of aldehyde-functionalized carbohydrates and hydrazide-functionalized poly(NIPAM-co-ADH),as well as the use of a double-barrel syringe for the formation of an in situ hydrazone cross-linked hydrogel. Abbreviations: AA, acrylic acid; ADH,adipic acid dihydrazide; AIBME, 2,2-azobisisobutyric acid dimethyl ester; CMC, carboxymethylcellulose; EDC, N′-ethyl-N-(3-(dimethylamino)-propyl)-carbodiimide, MAA, thioglycolic acid; and NIPAM, N-isopropylacrylamide. (Reproduced with permission from ref 88. Copyright 2012,American Chemical Society, Washington, DC.)

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■ AUTHOR INFORMATION

Corresponding Author*E-mail: rori0610@graduate.hku.hk.

ORCID

Wing-Fu Lai: 0000-0003-0585-6396Andrey L. Rogach: 0000-0002-8263-8141NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

The authors would like to thank Marie C. Lin, Cheng-Shen Hu,and Yau-Foon Tsui for their help and support during thepreparation of this manuscript.

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ACS Applied Materials & Interfaces Review

DOI: 10.1021/acsami.6b16120ACS Appl. Mater. Interfaces 2017, 9, 11309−11320

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